Methods of O-demethylation and N-deprotection

ABSTRACT

The present invention provides a method for N-deprotecting an opioid compound, a method for N-deprotecting and O-demethylating an opioid compound, a method for O-demethylating an opioid compound, and a method for O-demethylating a nonpeptidic delta agonist compound or an opioid compound having a tertiary amide with no significant reaction at amide groups.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent application is a divisional of U.S. patent application Ser.No. 09/194,510 filed on Jul. 6, 1999, now U.S. Pat. No. 6,291,675 whichis the U.S. national phase of PCT/US97/08628 filed on May 21, 1997,which claims priority to U.S. provisional patent application No.60/018,027 filed May 21, 1996, and U.S. provisional patent applicationno. 60/020,215 filed Jun. 21, 1996.

FIELD OF THE INVENTION

The present invention is directed to a method for the N-deprotection ofan opioid compound, a method for the N-deprotection and O-demethylationof an opioid compound, a method for the aromatic O-demethylation of anopioid compound, and a method for the selective O-demethylation of anonpeptidic delta agonist compound or an opioid compound having ahindered amide.

BACKGROUND OF THE INVENTION

An increasing demand for medicinal opiates, coupled with a finite supplyof raw materials from opium, has created a need for simple high yieldingprocedures for opiate transformations.

A 3-phenolic group is essential for the important pharmacologicalprofile of the opium alkaloids and their derivatives (opioid compounds).3-methyl ethers, such as codeine and thebaine, are the most widely usedstarting materials for opioid synthesis. Aromatic O-demethylation is akey step in the synthesis of virtually all opioid medical narcotics-andtheir antagonists. Current procedures involve the use of toxic andcarcinogenic reagents, such as boron tribromide, propane thiolate, andpotassium hydroxide. These reagents have a limited range ofapplicability and non-toxic alternatives are highly desirable.

Known methods of converting codeine to morphine are not entirelysatisfactory. Exposure of codeine or morphine to strong acid or alkalineconditions at higher temperatures has been found to promote substantialdecomposition of these opiates. Previously, codeine has been convertedto morphine by treatment with acids, such as pyridine hydrochloride, fora brief period at 220° C. or with the toxic boron tribromide. JournalMed. Chem., 20:164-65 (1977). Also, demethylation of a compound similarto codeine has been achieved by use of the diphenyl phosphide ion. TheO-demethylation of codeine has also been achieved by treatment withsodium propylmercaptide in dimethylformamide at 125° C. However, none ofthese previously known methods are desirable due to the need for toxicagents and/or the resulting substantial decomposition of the opiates.

Thebaine has no medicinal use in and of itself, but is a relativelyabundant widely used raw material derived from opium. Thebaine is thekey intermediate in the synthesis of many opiate derivatives. This isthe case for the oripavine derivatives initiated from the Diels-Alderadducts of thebaine. Oripavine is naturally occurring only in extremelyminor amounts, but is of interest since it may obviate the final anddifficult 3-O-methyl-ether cleavage in the synthesis of Diels-Alderderived narcotics. Journal of Med. Chem., 20:1074-77 (1975). No methodfor the direct transformation of thebaine to oripavine has beendiscovered, despite many attempts made over the course of seventy years.Even methods which are undesirable for other opioid conversions due totoxicity or decomposition of the opioid compounds do not work at all forthe conversion of thebaine to oripavine. For example, as mentionedabove, the O-demethylation of codeine has been achieved by treatment ofsodium propylmercaptide in dimethylformamide at 125° C. However, thissame procedure applied to thebaine did not yield oripavine. Journal Med.Chem., 20:165-66 (1977).

N-alkylation is also a key step in the synthesis of opioid compounds.Previously known methods that have been developed for N-alkylation haveresulted in low yields or were subject to hazards associated with theprocedures. For example, in the codeine to norcodeine conversion,N-deprotection of an intermediate carbamate has been accomplished usinghydrazine. However, this procedure is less than ideal due to thepotential presence of air-sensitive anhydrous hydrazine which isexplosive. J. Org. Chem., 40:1850-51 (1975).

O-demethylation and N-deprotection may occur simultaneously or one afterthe other under the proper conditions. Currently, O-demethylation andN-deprotection may occur simultaneously by subjecting the compound toalkaline conditions by heating with potassium hydroxide under vigorousconditions. J. Amer. Chem. Soc., 89:13 (1967). This reaction has beenfound to be unreliable at times and some compounds are not stable underthe vigorous conditions.

L-Selectride®, having the chemical name lithiumtri-sec-butylborohydride, has recently been reported as an efficientO-demethylating reagent for simple systems and stable compounds notnormally prone to rearrangements or decomposition when subjected tostrong acids or bases or hydride reagents. Tetrahedron Letters,35:8727-30 (1994). In contrast, opioid compounds can be very susceptibleto rearrangement and decomposition in the presence of strong acids andbases. For example, thebaine is known to be very sensitive to hydridereagents, the epoxide bridge being readily cleaved by hydride reagents.Thus, heretofore, hydride reagents, such as L-Selectride®, have not beenused as O-demethylating agents in opioid synthesis.

Never before has it been shown that trialkylborohydride reagents arecapable of N-deprotecting an N-protected opioid intermediate or thatthese hydride reagents can both N-deprotect and C-demethylate suchcompounds.

Accordingly, it is a principle object of the present invention toprovide a method for the N-deprotection of an N-protected opioidintermediate. It is another object of the invention to provide a methodfor both the N-deprotection and aromatic O-demethylation of theN-protected opioid intermediate without the use of toxic or carcinogenicreagents.

It is also a principal object of the present invention to provide amethod for the aromatic O-demethylation of opioids that can be carriedout without the use of toxic or carcinogenic reagents. It is a furtherobject of the invention to provide a method for the aromaticO-demethylation of opioids with a hydride reagent. It is yet anotherobject of the invention to provide a method for the aromaticO-demethylation of opioids in which the hydride reagent is a lithiumtrialkylborohydride.

It is a still further object of the present invention to provide amethod for the aromatic O-demethylation of codeine by treatment withL-Selectride® to obtain morphine.

It is another object of the present invention to directly convertthebaine to oripavine by treatment with L-Selectride®.

It is a further object of the present invention to provide a method forthe aromatic O-demethylation of a nonpeptidic delta agonist compound oran opioid compound having a tertiary amide group or other amide groupresistant to reaction with L-Selectride®.

These and other objects and advantages of the present invention, as wellas other inventive features, will be apparent from the description ofthe invention provided herein.

SUMMARY OF THE INVENTION

The present invention provides a method for the N-deprotection of anopioid compound with a hydride reagent. N-deprotection can beaccomplished by admixing an N-protected opioid intermediate of an opioidcompound with the hydride reagent and allowing the reagent to react. Thepresent invention further provides a method for the N-deprotection andO-demethylation of an opioid compound which includes admixing anN-protected opioid intermediate of an opioid compound with the hydridereagent.

The present invention further provides a method for the aromaticO-demethylation of opioid compounds with a hydride reagent. AromaticO-demethylation may be accomplished by admixing an opioid compound withthe hydride reagent and allowing the reagent to react, without the useof toxic or carcinogenic agents.

In each of these methods, the hydride reagent is a lithiumtrialkylborohydride, including lithium tri-sec-butylborohydride(L-Selectride®), lithium trisiamylborohydride (LS-Selectride®), andlithium triethylborohydride (SuperHydride®).

The present invention also provides a direct method for the conversionof thebaine to oripavine by contacting thebaine with lithiumtri-sec-butylborohydride (L-Selectride®).

The present invention still further provides a method for the aromaticdemethylation of a nonpeptidic delta agonist compound or an opioidcompound having a tertiary amide group with minimal or no reaction atthe amide group. The delta agonist compound or opioid compound isadmixed with lithium tri-sec-butylborohydride (L-Selectride®) or lithiumtrisiamylborohydride (LS-Selectride®).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the invention, it has been found that opioidcompounds and their intermediates are not decomposed by certain hydridereagents. Instead, hydride reagents are capable of N-deprotecting theN-protected opioid intermediates of the opioid compounds. Further, theseN-protected opioid intermediates may also be O-demethylated by thehydride reagents. In this way, important N-norphenolic intermediates canbe formed.

The opioid compounds which are suitable for use in the method of thisaspect of the present invention preferably have protective groups bondedto the nitrogen of the opioid compound. These protective groupsgenerally are present in the opioid compounds in place of the methylgroup commonly found in natural opiates.

The protective group bonded to the nitrogen of the opioid compounds maybe any protective group known in the art. Preferably, the protectivegroup and the nitrogen of the opioid compound form a cyanamide or acarbamate. Examples of other suitable compounds that can be used to formthe protective group, such as 2,2,2-trichloroethyl chloroformate andbenzyl or ethyl chloroformate, can be found in J. Org. Chem., 40:1850-51(1975) which is incorporated herein by reference.

In accordance with the present invention, N-methyl-containing opioidcompounds are preferably converted to intermediates, or N-protectedopioid intermediates, which possess an N-protected group that can becleaved by a hydride reagent. The opioid compounds may be converted toN-protected opioid intermediates by any method known in the art.

The N-protected opioid intermediate can then be reacted with the desiredhydride reagent. The method of the present invention permits theintroduction of other substituents, converting the N-methyl agonistopioid compounds to opiate antagonist compounds, pharmacologicallyimportant compounds.

Generally, the hydride reagent causes O-demethylation in addition to theN-deprotection of the opioid intermediates. In keeping with the methodof the present invention, the hydride reagent and N-protected opioidintermediate are admixed in a suitable vessel and aromatic methoxy groupand N-deprotects the N-protected group producing the desiredN-norphenolic compounds.

The aromatic O-demethylation and N-deprotection reactions may be carriedout over a wide temperature range, generally at any temperature whichpermits the opioid intermediate and the hydride reagent to react.Preferably the reaction is carried out at about 20° C. to about 70° C.While the reaction may be carried out at about room temperature, i.e.,about 20° C. to about 25° C., it is preferred that the reaction becarried out at an elevated temperature, i.e., from about 25° C. to about70° C., to increase the rate of the reaction. It is thus preferred thatthe reagents be refluxed to accomplish O-demethylation andN-deprotection. It is preferred that the reagents be refluxed in THF(tetrahydrofuran), as L-Selectride® is supplied in a solution of THF.Other solvents may be added for solubility reasons, preferably solventsthat do not react with L-Selectride® including, but not limited to,aliphatic ethers (tetrahydropyran, diethyl ether, t-butyl methyl ether),hydrocarbon solvents (hexanes, benzene, toluene), and chlorinatedaromatic solvents (chlorobenzene).

The hydride reagents suitable for use in the method of the presentinvention are those hydrides which do not decompose or causerearrangement of the N-protected opioid intermediate. Thus, suitablehydride reagents are desirably site specific to the aromatic O-methoxygroup and the N-protected group Satisfactory hydride reagents arelithium trialkylborohydrides which preferably includetrisiamylborohydride (LS-Selectride®), lithium triethylborohydride(SuperHydride®), and lithium tri-sec-butylborohydride (L-Selectride®).The most preferred hydride reagent is lithium tri-sec-butylborohydride.

The method of the present invention can be used for the N-deprotectionand O-demethylation of opioid compounds generally. By way ofillustration and not in limitation, the method of the present inventioncan be used to N-deprotect and O-demethylate the N-protected opioidintermediates of codeine, thevinols, indoles, oxycodone and derivativesthereof.

While not being bound to any particular theory, it is believed that thehydride reagents, particularly tri-sec-butylborohydride (L-Selectride®),act by allowing demethylation of the N-protected opioid intermediates,while the steric bulk prevents close approach to the C-5 and hencecleavage of the ether bridge. Thus, it is believed that the steric bulkof L-Selectride® minimizes reaction with the labile ether bridge.

Treatment of the N-protected opioid intermediates, e.g.,dihydrocodeinone-6-ketal, thevinols and the like, with a hydride reagentresults in aromatic O-demethylation and N-deprotection providingimportant N-norphenolic compounds which are key intermediates in thesynthesis of important opioid antagonists such as naltrexone, naloxoneand diprenorphine, and the important opioid analgesic buprenorphine.Examples of such O-demethylation and N-deprotection can be found inschemes I and II below.

The same O-demethylation and N-deprotection reactions occur with the14-hydroxy derivatives, e.g., indoles and oxycodone, to give the desiredN-norphenolic products, but the reaction is complicated by sideproducts.

Although O-demethylation and N-deprotection may occur simultaneously orin any sequence, it is believed that in many cases the N-deprotectionoccurs prior to the O-demethylation because the N-deprotection reactionis believed to occur more quickly than the O-demethylation reaction.

In some instances, O-demethylation may not occur, resulting in opioidcompounds that have only been N-deprotected. Further, because theN-deprotection reaction occurs far more rapidly than O-demethylation,perhaps even spontaneously at room temperature, the present inventionallows for selective N-deprotection of opioid compounds. Therefore, itis preferable that the reaction is not refluxed, but kept cold tominimize O-demethylation. If the reaction between the N-deprotectedopioid intermediate and the hydride reagent is halted afterN-deprotection occurs and prior to O-demethylation, opioid compounds maybe obtained which have not been O-demethylated, but which have beenselectively N-deprotected. The reaction with the hydride reagent may behalted by any means known in the art. For example, opioid compoundswhich may be selectively N-deprotected include, but are not limited to,N-protected opioid intermediates of thevinols, indoles, codeine,oxycodone and derivatives thereof. An example of the N-deprotection of17-carbomethoxynorcodeinone to norcodeine is set forth in Scheme IIIbelow.

In accordance with another embodiment of the present invention, thehydride reagents are capable of O-demethylating the opioid compounds. Inkeeping with this aspect of the present invention, the hydride reagentand opioid compound are admixed in a suitable vessel and allowed toreact. The hydride reagent demethylates the aromatic methoxy groupleaving the desired phenol derivative.

The aromatic O-demethylation reaction may likewise be carried out over awide temperature range, i.e, from about 20° C. to about 70° C. While thereaction may be carried out at about room temperature, i.e., about 20°C. to about 25° C., it is preferred that the reaction be carried out atelevated temperatures to increase the rate of the reaction. It is thuspreferred that the mixture of reagents be refluxed to accomplishO-demethylation.

The hydride reagents suitable for use in the method of aromaticO-demethylation are likewise those hydride reagents which do notdecompose or cause rearrangement of the opioid compound and aredesirably site specific to the aromatic methoxy group. Satisfactoryhydride reagents include the lithium trialkylborohydrides, such astrisiamylborohydride (LS-Selectride®), lithium triethylborohydride(SuperHydride®), and lithium tri-sec-butylborohydride (L-Selectride®).The preferred hydride reagent is lithium tri-sec-butylborohydride.

The method of the present invention can be used for the aromaticO-demethylation of opioid compounds generally. By way of illustrationand not in limitation, the method of the present invention may be usedto O-demethylate thebaine, thevinols, indoles, codeine, oxycodone andthe like.

The discovery that thebaine can be converted to oripavine with a hydridereagent is an unexpected discovery of the present invention. Despitemany efforts over more than sixty years, there has been no direct methodfor the O-demethylation of thebaine to oripavine, due in large part tothe sensitivity of the allylic aromatic ether to acids, bases andnucleophiles. Since oripavine occurs in opium in extremely minoramounts, while thebaine is relatively abundant by comparison, directO-demethylation of thebaine in accordance with the invention offers apractical synthesis of oripavine. The direct synthesis of oripavineresulting from the admixture of thebaine and L-Selectride® is set forthin Scheme IV:

The ready availability of oripavine obtained by treatment of thebainewith L-Selectride® allows the synthesis of compounds currently preparedfrom thebaine without the need for further Q-demethylation. Syntheses ofimportant opioids, such as diprenorphine and naltrexone, from oripavinecan be easily achieved by application of the present invention.

Some opioid compounds, such as thevinols, are sensitive to acid whichoften makes O-demethylation difficult. However, treatment of thevinolswith L-Selectride® results in clean conversions to the correspondingphenols (orvinols). Representative reactions are described in Schemes Vand VI.

Indoles are important opioid compounds due to their δ opioid receptorselectivity. This receptor has been associated with many biologicalprocesses, thereby providing for δ selective medication. Successfularomatic O-demethylation in the indole series offers an importantalternative synthesis for the phenols derived from indoles. Treatmentwith L-Selectride® provides demethylation of the indoles to thecorresponding phenols as shown in Scheme VII.

The O-demethylation of codeine to morphine can be accomplishedsatisfactorily without toxic or carcinogenic reagents usingL-Selectride® according to Scheme VIII.

The conversion of oxycodone to oxymorphone is an important commercialtransformation which is performed with boron tribromide. Thistransformation can also be made with L-Selectride as shown in Scheme IX,a significant improvement in both convenience and toxicityconsiderations.

Another aspect of the present invention provides a method for theO-demethylation of nonpeptidic delta agonists, compounds which arecapable of selectively binding to the opiate δ receptor. These compoundscan be O-demethylated with minimal or no reaction at the amide byadmixture with a hydride reagent. The hydride reagent is preferablylithium tri-sec-butylborohydride (L-Selectride®) or lithiumtrisiamylborohydride (LS-Selectride®). A representative reaction isshown in Scheme X.

The use of lithium triethylborohydride (SuperHydride®) in this aspect ofthe invention is not desirable because it is known to cleave amidegroups. However, it is believed that the reason lithiumtri-sec-butylborohydride and lithium trisiamylborohydride O-demethylatewithout cleavage of the amide is because of the large size of thelithium tri-sec-butylborohydride and lithium trisiamylborohydridemolecules.

BW373U86, shown in Scheme X, is a novel non-peptide δ opioid receptorracemic agonist which is useful in the discovery of new probes for the δreceptor system. The method of the present invention is suitable for usewith any nonpeptide delta agonist compound having a related structureand a tertiary amide group or an amide group that is resistant toreaction with L-Selectride®. The hindered amide group may be any amidegroup that is resistant to reaction with L-Selectride® including, butnot limited to, amides that are N-N-disubstituted with alkyl, arylalkylor aryl groups. Preferable compounds include (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide(SNC80) and other compounds having a structure similar to SNC80 and ahindered tertiary amide group or amide group that is resistant toreaction with L-Selectride®. This method is also applicable to opioidcompounds having a tertiary amide group and compounds with opioid-likestructures having a tertiary amide groups resistant to reaction withL-Selectride®. Again, the hindered amide group may be any amide groupthat is resistant to reaction with L-Selectride® including, but notlimited to, amides that are N,-N-disubstituted with alkyl, arylalkyl, oraryl groups.

Again, the aromatic O-demethylation may be carried out over a widetemperature range. The reaction may be carried out at room temperature,i.e., about 20° C. to about 25° C., but it is preferred that thereaction be carried out at an elevated temperature, i.e., from aboutroom temperature up to about 70° C. It is preferred that the reagents berefluxed in THF to accomplish the O-demethylation. Other solvents may beadded for solubility reasons, preferably solvents that do not react withL-Selectride® including, but not limited to, aliphatic ethers(tetrahydropyran, diethyl ether, t-butyl methyl ether), hydrocarbonsolvents (hexanes, benzene, toluene), and chlorinated aromatic solvents(chlorobenzene).

General Synthetic Methods

The lithium trialkylborohydrides, as is known, are extremely reactivewith oxygen and water. See, Aldrich Catalog Handbook of Fine Chemicals,p. 908 (1996-97). Accordingly, each of the reactions described above arepreferably carried out in an inert atmosphere, such as argon, nitrogen,or the like, as one skilled in the art would readily appreciate. B. S.Furniss et al., Vogle's Textbook of Practical Organic Chemistry, LongmanScientific and Technical, John Wiley & Sons, Inc., N.Y., pp. 120-131(5^(th) ed.1989).

After the reaction is complete according to any of the methods describedherein, the desired end product is isolated and purified by techniqueswell known to those skilled in the art. Accordingly, after quenching ofthe excess hydride reagent with water, the mixture is basified to pH 14with preferably, potassium hydroxide or sodium hydroxide. The reactionsolvent (e.g., tetrahydrofuran) is removed from the reaction vessel,preferably under reduced pressure. The reaction mixture is then washedwith a known organic solvent. Suitable solvents include ethers,halogenated solvents such as dichloromethane, chloroform, and the like,and mixtures of halogenated solvents and alcohols, including methanol,ethanol, propanols, and the like, as described, for example, in JournalMed. Chem., 18:1074-77 (1975), which is incorporated by referenceherein.

The washed product mixture is then acidified to a pH range of from about1 to about 3. The acid may be a dilute aqueous solution of organic acidsuch as citric acid, acetic acid and formic acid, or a dilute aqueoussolution of inorganic acid, such as hydrochloric acid, phosphoric acid,sulfuric acid and hydrobromic acid.

The acidified reaction product is then rebasified to a pH in the rangeof from about 7 to about 10, preferably about 9. Suitable basificationagents include concentrated aqueous ammonia solution, an aqueoussolution of sodium bicarbonate, and the like.

If the end product is not soluble in the aqueous base layer solution,then the reaction is simply quenched with water, followed byacidification to pH 1, then basification to pH 7-10.

The phenolic product is then extracted from the aqueous layer usingethers, halogenated solvents such as dichloromethane, chloroform, andthe like, mixtures of halogenated solvents and alcohols, includingmethanol, ethanol, propanols, and the like, ethyl acetate, and aromaticsolvents such as benzene, toluene and the like.

The purified end product is obtained by crystallization orchromatography by techniques well known in the art, such as described inB. S. Furniss et al., Vogle's Textbook of Practical Organic Chemistry,Longman Scientific and Technical, John Wiley & Sons, Inc., N.Y., pp.131-235 (5^(th) ed.1989) which is incorporated by reference herein.

It will be appreciated by those skilled in the art that the aromaticO-demethylation, N-deprotection, combined O-demethylation andN-deprotection, and selective O-demethylation of nonpeptidic deltaagonists and opioid compounds having a hindered tertiary amide orotherwise unreactive amide processed as described herein, can be appliedto derivatives of the opioid compounds as well. Thus, opioid compoundsthat have been derivatized with organic moieties such as alkyls,alkenyls, alkynyls, aryls, arylalkyls, ethers, aromatic halogens, andthe like that are inert to reaction with hydride reagents, can also beO-demethylated and/or N-deprotected in accordance with the methodsdescribed above with the lithium trialkylborohydrides, especially thosedescribed above.

Further, the reducing properties of the lithium trialkylborohydrides,such as L-Selectride®, can be exploited by reducing opioid compoundsthat have been derivatized with organic moieties, such as carbonyl orthe like, with simultaneous O-demethylation. For example, in theconversion of dihydrocodeinone to dihydromorphine, dihydrocodeinone isboth reduced and O-demethylated to obtain dihydromorphine.

The present inventive methods are further described in the context ofthe following examples. These examples serve to illustrate further thepresent invention and are not intended to limit the scope of theinvention.

EXAMPLE I

This example illustrates the synthesis ofdihydronormorphinone-6-ethylene ketal by N-deprotection andO-demethylation of a carbamate (an N-protected opioid intermediate) withtri-sec-butylborohydride (L-Selectride®).

Under an inert atmosphere (argon), a mixture of the carbamate(17-carbomethoxydihydronorcodeinone-6-ethylene ketal) (520 mg, 1.3 mmol)and L-Selectride (1 M in THF, 12.5 ml) was heated at reflux for 4.5hours. After cooling to room temperature, the reaction was quenched withwater (10 ml) and NaOH (1 M, 5 ml). The THF was removed under reducedpressure and the mixture was washed with dichloromethane, acidified(pH 1) with hydrochloric acid (10%) and rebasified (pH 9) with ammoniasolution. The aqueous solution was saturated with salt and extractedwith chloroform/methanol (3:1). After removal of the solvents, theproduct was isolated as the hydrochloride salt from methanol (280 mg,59%).

Mp.>300° C. (dec.); δ_(H) (300 MHz, D₂O) (HCl salt) 2.98 (1H, d j 18.5Hz, 10β-H), 4.70 (1H, δ, 5-H), 6.76 (1H, d j 8.2 Hz, 1-H), 6.82 (1H, d j8.2 Hz, 2-H); m/z (CS LSMIS) 316 (M+1, 100%); Calc. For C₁₈H₂₂NO₄Cl C61.45 H 6.30 N 3.98, found C 61.28 H 6.30 N 3.93.

EXAMPLE II

This example illustrates the synthesis of norcodeine from17-Carbomethoxynorcodeine by N-deprotection (without O-demethylation)with lithium tri-sec-butylborohydride (L-Selectride®) (see Scheme III).

Lithium tri-sec-butylborohydride (L-Selectride®) (1M in THF, 5 ml) wasadded to a cooled (0-5° C.) solution of 17-carbomethoxynorcodeine (300mg, 0.87 mmol) in dry THF (2 ml) under an atmosphere of argon. Thereaction mixture was allowed to warm to room temperature and thenstirred for 24 hours. After quenching the reaction with water (10 ml),the THF was removed under reduced pressure and the remaining aqueousmixture acidified to pH 1-2 with citric acid (15%) and washed withchloroform (2×30 ml). After basification with ammonia solution, themixture was extracted into chloroform (3×50 ml) which was then washedwith brine and dried (Na₂SO₄). Purification as the hydrochloride saltfrom water gave norcodeine hydrochloride trihydrate (275 mg, 83%).

Mp>300° C.; δ_(H) (300 MHz, CDCl₃) 3.61-3.67 (1H, s br), 3.81 (3H, s,3-OCH₃), 4.16-4.21 (1H, m, 6-H), 4.84 (1H, d j 6.2 Hz, 5-H), 522-5.29(1H, m, 7-H), 5.68-5.76 (1H, m, 8-H), 6.58 (1H, d j 8.2 Hz, 1-H), 6.64(1H, d j 8.2 Hz, 2-H; m/z (EI) 285 (M+, 100%).

EXAMPLE III

This example illustrates the synthesis of oripavine from thebaine byadmixing thebaine with lithium tri-sec-butylborohydride(L-Selectride®)(See Scheme IV).

Under an inert atmosphere (argon), a mixture of thebaine (3.64 g, 11.7mmol) and lithium tri-sec-butylborohydride (L-Selectride®) (1M in THF,60 ml) was stirred at room temperature for 14 days. The reaction wasquenched with water (50 ml) followed by aqueous NaOH solution (15%, 30ml) and the THF removed under reduced pressure. The resulting mixturewas washed with dichloromethane (2×50 ml) and acidified (pH 1) withhydrochloric acid (10%). After basification with ammonia solution (pH9), the mixture was extracted into chloroform (3×60 ml) and the organicphase washed with brine (100 ml) and dried (Na₂SO₄). Removal of thesolvent under reduced pressure gave the crude oripavine product.Crystallization as the oxalate salt from methanol gave oripavine oxalate(1.69 g, 35%).

Mp. 198-200° C. (dec.); δ_(H) (300 MHz, CDCl₃) 2.45 (3H, s, NCH₃), 3.31(1H, d j 18.5 H_(z), 10β-H), 3.59 (3H, s, 6-OCH₃), 5.04 (1H, d j 6.2 Hz,8-H), 5.28 (1H, s, 5-H), 5.55 (1H, d j 6.2 Hz, 7-H), 6.54 (1H, d j 8.2Hz, 1-H) 6.62 (1H, d j 8.2 Hz, 2-H); m/z (CI) 298 (M+1, 100%); Calc. ForC₂₀H₂₁NO₇. 1.5 H₂O C 57.96 H 5.84 N 3.38, found C 58.22 H 5.82 N 3.41.

The original dichloromethane extracts obtained above were washed withwater (2×100 ml), followed by brief treatment with basic peroxide. Theorganic layer was separated, washed with brine (100 ml) and dried(Na₂SO₄). Removal of the solvent under reduced pressure gave a brownfoam. Crystallization as the natural tartrate salt from methanol gavethebaine tartrate (270 mg, 5%).

EXAMPLE IV

This example illustrates a second method for the synthesis of oripavinefrom thebaine by admixing thebaine with tri-sec-butylborohydride(L-Selectride®) (See Scheme IV).

The method of Example 1 above was followed, but 2 equivalents oftri-sec-butylborohydride (L-Selectride®) were used and the mixture wasrefluxed for 30 minutes to give oripavine oxalate hydrate (23%) andthebaine tartrate (31%).

EXAMPLE V

This example illustrates the synthesis of oxymorphone from oxycodone byadmixing oxycodone with tri-sec-butylborohydride (L-Selectride®) (SeeScheme IX).

A solution of oxycodone HCl (2.5 g, 6.9 mmol), ethylene glycol (5 ml)and catalytic toluene sulfonic acid in dry toluene (200 ml) was heatedat reflux for 1 hour with azeotropic removal of water. After cooling,the solution was basified with ammonia solution and partitioned betweenwater and chloroform and the aqueous phase was further extracted withchloroform. The organic extracts were washed with brine and dried(Na₂SO₄). Removal of the solvent gave the crude ketal (2.46 g).

Under an inert atmosphere (argon), a mixture of the ketal andtri-sec-butylborohydride (L-Selectride®) (0.5M in THF, 40 ml) was heatedat reflux for 23 hours. The reaction was quenched with water (20 ml)followed by aqueous NaOH solution (15%, 15 ml) and the THF removed underreduced pressure. The resulting mixture was washed with dichloromethane(2×20 ml) and acidified (pH 1) with hydrochloric acid (10%). Afterbasification with ammonia solution (pH 9), the mixture was extractedinto chloroform (3×40 ml) and the organic phase washed with brine anddried (Na₂SO₄). Removal of the solvent under reduced pressure gave acrude foam. The foam was redissolved in methanol (40 ml), water (20 ml)and hydrochloric acid (20%, 20 ml) and the solution refluxed for 1 hour.After cooling, the reaction was diluted with water (50 ml), basifiedwith ammonia (pH 9), saturated with salt, and extracted into chloroform(3×70 ml). After removal of the solvent under reduced pressure, theproduct was crystallized as the oxalate salt from ethanol. (2.11 g,78%).

Mp.247-248° C. (dec.) δ_(H) (300 MHz, CDCl₃) 2.41 (3H, s, NCH₃), 3.15(1H, d j 18.5H_(z), 10β-H), 4.68 (1H, s, 5-H), 6.60 (1H, d j 8.2 Hz,1-H), 6.72 (1H, d j 8.2 Hz, 2-H); m/z (CI) 302 (M+1, 100%); Calc. forC₁₉H₂₁NO₈ C58.31 H 5.41 N 3.58, found C 57.94 H 5.44 N 3.56.

EXAMPLE VI

This example illustrates the synthesis of naltrindole.

Under an inert atmosphere, (argon), a mixture of the methyl ether (240mg, 0.56 mmol)(See Scheme VII) and tri-sec-butylborohydride(L-Selectride®) (1M in THF, 2.5 ml) was heated at reflux for 4 h. Aftercooling the reaction was quenched with water (10 ml) and NaOH (15%, 10ml). After removal of the THF, the aqueous solution was extracted withdichloromethane (2×20 ml). The organic extracts were then washed withbrine (30 ml), dried (Na₂SO₄) and the solvent removed under reducedpressure to give a foam. Formation of the hydrochloride salt inmethanol, followed by replacement of the solvent with isopropanol, gavethe salt (225 mg, 82%).

Mp. <275° C. (dec.); δ_(H) (300 MHz, CDCl₃) 0.12-2.00 (2H, m), 0.53-0.62(2H, m), 0.81-0.95 (1H, m), 3.12 (1H, d j 18.5 HZ, 10-βH), 5.69 (1H, s,5-H), 6.50 (1H, d j 8.2 Hz, 1-H), 6.58 (1H, d j 8.2 Hz, 2-H), 6.96-7.42(4H, m, Ar—H), 8.22 (1H, br s, N—H); m/z (Cl) 415 (M+1, 64%); Calc. ForC₂₆H₂₇N₂O₃Cl.CH₃OH C 67.14 H 6.47 N 5.80, found C 66.93 H 6.28 N 5.71.

EXAMPLE VII

This example illustrates the synthesis of the delta agonist (+)-BW373U86by O-demethylation without significant reaction at the amide group withtri-sec-butylborohydride (L-Selectride®) (See Scheme X).

Under an inert atmosphere (argon), a mixture of SNC80, as shown inScheme III (740 mg, 1.65 mmol), and lithium tri-sec-butylborohydride(L-Selectride®) (1M in THF, 5 ml) was heated at reflux for 6 hours,cooled to room temperature and then quenched with water (20 ml). Afterremoval of the THF under reduced pressure, the mixture was acidified(pH 1) with hydrochloric acid (10%), rebasified (pH 9) with ammoniasolution and extracted into dichloromethane (3×40 ml). The organicextracts were then washed with brine (2×50 ml), dried (Na₂SO₄) and thesolvent removed under reduced pressure to give the crude product. Columnchromatography (Silica, CH₂Cl₂:EtOAc 1:1, 0.5% NH₃) gave the desiredproduct (360 mg, 50%).

Ditoluoyl-L-tartrate salt; mp 151-153° C.; δ_(H) (300 MHz, CDCl₃) 0.95(3H, d j 6.0 Hz, CCH₃) 1.15-1.28 (9H, m), 1.91 (1H, br t), 2.15 (1H, brt), 5.11-5.24 (3H, m), 5.78-5.93 (1H, m), 6.57 (1H, S), 6.61-6.67 (2H,m), 7.07-7.13 (1H, m), 7.28 (2H, d j 8.2 Hz), 7.42 (2H, d j 8.2 HZ); m/z(Cl) 436 (M+1, 76%); Calc. For C₂₆H₂₇N₂O₃Cl.CH₃OH C 67.14 H 6.47 N 5.80,found C 66.93 H 6.28 N 5.71. Calc. For C₄₇H₅₅N₃O₁₀ 1.5H₂O C 66.49 H 6.89N 4.95, found C 66.58 H 6.75 N 4.90.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A method for the N-deprotection of an opioidcompound comprising admixing an N-protected opioid intermediate of saidopioid compound and a hydride reagent selected from the group consistingof lithium trialkylborohydrides.
 2. The method of claim 1, wherein saidlithium trialkylborohydride is selected from the group consisting oflithium tri-sec-butylborohydride, lithium trisiamylborohydride, andlithium triethylborohydride.
 3. The method of claim 1, wherein saidopioid compound is selected from the group consisting of morphine,thevinols, orvinols, indoles, codeine, oxycodone, oxymorphone, andderivatives thereof.
 4. The method of claim 1, further comprisinghalting a reaction between the N-protected opioid intermediate of saidopioid compound and the hydride reagent before O-demethylation occurs.5. A method for the aromatic O-demethylation and N-deprotection of anopioid compound comprising admixing an N-protected opioid intermediateof said opioid compound and a hydride reagent selected from the groupconsisting of lithium trialkylborohydrides.
 6. The method of claim 5,wherein said lithium trialkylborohydride is selected from the groupconsisting of lithium tri-sec-butylborohydride, lithiumtrisiamylborohydride, and lithium triethylborohydride.
 7. The method ofclaim 5, wherein said opioid compound is selected from the groupconsisting of the N-protected intermediates of codeine, thevinols,indoles, oxycodone, and derivatives thereof.
 8. A method of making anor-phenol comprising admixing an N-protected opioid intermediate of anopioid compound and a hydride reagent selected from the group consistingof lithium tri-sec-butylborohydride, lithium trisiamylborohydride, andlithium triethylborohydride.
 9. The method of claim 8, wherein saidhydride reagent is lithium tri-sec-butylborohydride.
 10. The method ofclaim 8, wherein said opioid compound is selected from the groupconsisting of the N-protected intermediates of codeine, thevinols,indoles, oxycodone, and derivatives thereof.